Deficiency in metabolic regulators PPARγ and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration

Douglas W. Strand, David Degraff, Ming Jiang, Mansoureh Sameni, Omar E. Franco, Harold D. Love, William J. Hayward, Opal Lin-Tsai, Anne Y. Wang, Justin M.M. Cates, Bonnie F. Sloane, Robert J. Matusik, Simon W. Hayward

Research output: Contribution to journalArticle

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Abstract

Hindgut-derived endoderm can differentiate into rectal, prostatic, and bladder phenotypes. Stromal-epithelial interactions are crucial for this development; however, the precise mechanisms by which epithelium responds to stromal cues remain unknown. We have previously reported ectopic expression of peroxisome proliferator-activated receptor-γ2 (PPARγ2) increased androgen receptor expression and promoted differentiation of mouse prostate epithelium. PPARγ is also implicated in urothelial differentiation. Herein we demonstrate that knockdown of PPARγ2 in benign human prostate epithelial cells (BHPrEs) promotes urothelial transdifferentiation. Furthermore, in vitro and in vivo heterotypic tissue regeneration models with embryonic bladder mesenchyme promoted urothelial differentiation of PPARγ2-deficient BHPrE cells, and deficiency of both PPARγ isoforms 1 and 2 arrested differentiation. Because PTEN deficiency is cooperative in urothelial pathogenesis, we engineered BHPrE cells with combined knockdown of PPARγ and PTEN and performed heterotypic recombination experiments using embryonic bladder mesenchyme. Whereas PTEN deficiency alone induced latent squamous differentiation in BHPrE cells, combined PPARγ and PTEN deficiency accelerated the development of keratinizing squamous metaplasia (KSM). We further confirmed via immunohistochemistry that gene expression changes in metaplastic recombinants reflected human urothelium undergoing KSM. In summary, these data suggest that PPARγ isoform expression provides a molecular basis for observations that adult human epithelium can be transdifferentiated on the basis of heterotypic mesenchymal induction. These data also implicate PPARγ and PTEN inactivation in the development of KSM.

Original languageEnglish (US)
Pages (from-to)449-459
Number of pages11
JournalAmerican Journal of Pathology
Volume182
Issue number2
DOIs
StatePublished - Feb 1 2013

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Peroxisome Proliferator-Activated Receptors
Metaplasia
Regeneration
Prostate
Epithelial Cells
Urinary Bladder
Epithelium
Mesoderm
Protein Isoforms
Drive
Urothelium
Endoderm
Androgen Receptors
Genetic Recombination
Cues
Immunohistochemistry
Phenotype
Gene Expression

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Strand, Douglas W. ; Degraff, David ; Jiang, Ming ; Sameni, Mansoureh ; Franco, Omar E. ; Love, Harold D. ; Hayward, William J. ; Lin-Tsai, Opal ; Wang, Anne Y. ; Cates, Justin M.M. ; Sloane, Bonnie F. ; Matusik, Robert J. ; Hayward, Simon W. / Deficiency in metabolic regulators PPARγ and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration. In: American Journal of Pathology. 2013 ; Vol. 182, No. 2. pp. 449-459.
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title = "Deficiency in metabolic regulators PPARγ and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration",
abstract = "Hindgut-derived endoderm can differentiate into rectal, prostatic, and bladder phenotypes. Stromal-epithelial interactions are crucial for this development; however, the precise mechanisms by which epithelium responds to stromal cues remain unknown. We have previously reported ectopic expression of peroxisome proliferator-activated receptor-γ2 (PPARγ2) increased androgen receptor expression and promoted differentiation of mouse prostate epithelium. PPARγ is also implicated in urothelial differentiation. Herein we demonstrate that knockdown of PPARγ2 in benign human prostate epithelial cells (BHPrEs) promotes urothelial transdifferentiation. Furthermore, in vitro and in vivo heterotypic tissue regeneration models with embryonic bladder mesenchyme promoted urothelial differentiation of PPARγ2-deficient BHPrE cells, and deficiency of both PPARγ isoforms 1 and 2 arrested differentiation. Because PTEN deficiency is cooperative in urothelial pathogenesis, we engineered BHPrE cells with combined knockdown of PPARγ and PTEN and performed heterotypic recombination experiments using embryonic bladder mesenchyme. Whereas PTEN deficiency alone induced latent squamous differentiation in BHPrE cells, combined PPARγ and PTEN deficiency accelerated the development of keratinizing squamous metaplasia (KSM). We further confirmed via immunohistochemistry that gene expression changes in metaplastic recombinants reflected human urothelium undergoing KSM. In summary, these data suggest that PPARγ isoform expression provides a molecular basis for observations that adult human epithelium can be transdifferentiated on the basis of heterotypic mesenchymal induction. These data also implicate PPARγ and PTEN inactivation in the development of KSM.",
author = "Strand, {Douglas W.} and David Degraff and Ming Jiang and Mansoureh Sameni and Franco, {Omar E.} and Love, {Harold D.} and Hayward, {William J.} and Opal Lin-Tsai and Wang, {Anne Y.} and Cates, {Justin M.M.} and Sloane, {Bonnie F.} and Matusik, {Robert J.} and Hayward, {Simon W.}",
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Strand, DW, Degraff, D, Jiang, M, Sameni, M, Franco, OE, Love, HD, Hayward, WJ, Lin-Tsai, O, Wang, AY, Cates, JMM, Sloane, BF, Matusik, RJ & Hayward, SW 2013, 'Deficiency in metabolic regulators PPARγ and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration', American Journal of Pathology, vol. 182, no. 2, pp. 449-459. https://doi.org/10.1016/j.ajpath.2012.10.007

Deficiency in metabolic regulators PPARγ and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration. / Strand, Douglas W.; Degraff, David; Jiang, Ming; Sameni, Mansoureh; Franco, Omar E.; Love, Harold D.; Hayward, William J.; Lin-Tsai, Opal; Wang, Anne Y.; Cates, Justin M.M.; Sloane, Bonnie F.; Matusik, Robert J.; Hayward, Simon W.

In: American Journal of Pathology, Vol. 182, No. 2, 01.02.2013, p. 449-459.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Deficiency in metabolic regulators PPARγ and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration

AU - Strand, Douglas W.

AU - Degraff, David

AU - Jiang, Ming

AU - Sameni, Mansoureh

AU - Franco, Omar E.

AU - Love, Harold D.

AU - Hayward, William J.

AU - Lin-Tsai, Opal

AU - Wang, Anne Y.

AU - Cates, Justin M.M.

AU - Sloane, Bonnie F.

AU - Matusik, Robert J.

AU - Hayward, Simon W.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - Hindgut-derived endoderm can differentiate into rectal, prostatic, and bladder phenotypes. Stromal-epithelial interactions are crucial for this development; however, the precise mechanisms by which epithelium responds to stromal cues remain unknown. We have previously reported ectopic expression of peroxisome proliferator-activated receptor-γ2 (PPARγ2) increased androgen receptor expression and promoted differentiation of mouse prostate epithelium. PPARγ is also implicated in urothelial differentiation. Herein we demonstrate that knockdown of PPARγ2 in benign human prostate epithelial cells (BHPrEs) promotes urothelial transdifferentiation. Furthermore, in vitro and in vivo heterotypic tissue regeneration models with embryonic bladder mesenchyme promoted urothelial differentiation of PPARγ2-deficient BHPrE cells, and deficiency of both PPARγ isoforms 1 and 2 arrested differentiation. Because PTEN deficiency is cooperative in urothelial pathogenesis, we engineered BHPrE cells with combined knockdown of PPARγ and PTEN and performed heterotypic recombination experiments using embryonic bladder mesenchyme. Whereas PTEN deficiency alone induced latent squamous differentiation in BHPrE cells, combined PPARγ and PTEN deficiency accelerated the development of keratinizing squamous metaplasia (KSM). We further confirmed via immunohistochemistry that gene expression changes in metaplastic recombinants reflected human urothelium undergoing KSM. In summary, these data suggest that PPARγ isoform expression provides a molecular basis for observations that adult human epithelium can be transdifferentiated on the basis of heterotypic mesenchymal induction. These data also implicate PPARγ and PTEN inactivation in the development of KSM.

AB - Hindgut-derived endoderm can differentiate into rectal, prostatic, and bladder phenotypes. Stromal-epithelial interactions are crucial for this development; however, the precise mechanisms by which epithelium responds to stromal cues remain unknown. We have previously reported ectopic expression of peroxisome proliferator-activated receptor-γ2 (PPARγ2) increased androgen receptor expression and promoted differentiation of mouse prostate epithelium. PPARγ is also implicated in urothelial differentiation. Herein we demonstrate that knockdown of PPARγ2 in benign human prostate epithelial cells (BHPrEs) promotes urothelial transdifferentiation. Furthermore, in vitro and in vivo heterotypic tissue regeneration models with embryonic bladder mesenchyme promoted urothelial differentiation of PPARγ2-deficient BHPrE cells, and deficiency of both PPARγ isoforms 1 and 2 arrested differentiation. Because PTEN deficiency is cooperative in urothelial pathogenesis, we engineered BHPrE cells with combined knockdown of PPARγ and PTEN and performed heterotypic recombination experiments using embryonic bladder mesenchyme. Whereas PTEN deficiency alone induced latent squamous differentiation in BHPrE cells, combined PPARγ and PTEN deficiency accelerated the development of keratinizing squamous metaplasia (KSM). We further confirmed via immunohistochemistry that gene expression changes in metaplastic recombinants reflected human urothelium undergoing KSM. In summary, these data suggest that PPARγ isoform expression provides a molecular basis for observations that adult human epithelium can be transdifferentiated on the basis of heterotypic mesenchymal induction. These data also implicate PPARγ and PTEN inactivation in the development of KSM.

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